State-of-the-art methods for exposure-health studies: Results from the exposome data challenge event

The exposome recognizes that individuals are exposed simultaneously to a multitude of different environmental factors and takes a holistic approach to the discovery of etiological factors for disease. However, challenges arise when trying to quantify the health effects of complex exposure mixtures. Analytical challenges include dealing with high dimensionality, studying the combined effects of these exposures and their interactions, integrating causal pathways, and integrating high-throughput omics layers. To tackle these challenges, the Barcelona Institute for Global Health (ISGlobal) held a data challenge event open to researchers from all over the world and from all expertises. Analysts had a chance to compete and apply state-of-the-art methods on a common partially simulated exposome dataset (based on real case data from the HELIX project) with multiple correlated exposure variables (P > 100 exposure variables) arising from general and personal environments at different time points, biological molecular data (multi-omics: DNA methylation, gene expression, proteins, metabolomics) and multiple clinical phenotypes in 1301 mother–child pairs. Most of the methods presented included feature selection or feature reduction to deal with the high dimensionality of the exposome dataset. Several approaches explicitly searched for combined effects of exposures and/or their interactions using linear index models or response surface methods, including Bayesian methods. Other methods dealt with the multi-omics dataset in mediation analyses using multiple-step approaches. Here we discuss features of the statistical models used and provide the data and codes used, so that analysts have examples of implementation and can learn how to use these methods. Overall, the exposome data challenge presented a unique opportunity for researchers from different disciplines to create and share state-of-the-art analytical methods, setting a new standard for open science in the exposome and environmental health field

High frequency measurements of CO2 and CH4 fluxes in a temperate peatland dominated by Molinia caerulea (La Guette, France)

International audiencePeatlands act as a powerful carbon (C) sink. This specificity results from their particular environment, composed of Shagnum mosses, and the acidic state of the soil combined with a high water saturation that strongly limit organic matter decomposition. Future natural and anthropogenic global changes are expected to modify peatlands functioning and their species composition, which could reverse their valuable role in C sequestration and thus in climate change mitigation. However, the response of peatlands to these biotic changes, and thus the variability of greenhouse gas fluxes, remains poorly characterized and understood. We investigated CO2 and CH4 emissions in the La Guette peatland, an acidic fen located in the center of France, thanks to an Eddy-covariance station that was installed in the ecosystem in early 2017. In addition, this site is applying for the ICOS network labelling as an associated site, and follows the ICOS recommendations. Our main concern is that La Guette peatland is submitted to a strong domination by a herbaceous plant, Molinia caerulea, and a ericaceous shrub, Erica tetralix, which are suspected to modify the C dynamic of the ecosystem. From January 2017 to September 2019, CO2 and CH4 fluxes to the atmosphere ranged from to -19.46 to 19.73 µmol m-2 s-1 and from -0.12 to 0.42 µmol m-2 s-1, respectively. Mean CO2 flux for 2017, 2018 and 2019 were respectively 1.13, 1.08 and 0.44 µmol m-2 s-1. Carbon balance of the ecosystem since the beginning of 2017 has been evaluated to 982 gC m-², suggesting that the peatland acted as a source of C over these three last years. In a larger scale, this Eddy covariance station is a part of a French Peatland Observatory Service, and is included in a network of three tower fluxes deployed in three contrasted French peatlands. In the long term, this Eddy-covariance network will provide important data that will help to understand the evolution of the C balance in temperate peatlands with global changes

High frequency measurements of CO2 and CH4 in a temperate peatland dominated by Molinia caerulea (La Guette, France)

International audiencePeatlands act as a powerful carbon (C) sink. This specificity results from their particular environment, composed of Shagnum mosses, and the acidic state of the soil combined with a high water saturation that strongly limit organic matter decomposition. Future natural and anthropogenic global changes are expected to modify peatlands functioning and their species composition, which could reverse their valuable role in C sequestration and thus in climate change mitigation. However, the response of peatlands to these biotic changes, and thus the variability of greenhouse gas fluxes, remains poorly characterized and understood. We investigated CO2 and CH4 emissions in the La Guette peatland, an acidic fen located in the center of France, thanks to an Eddy-covariance station that was installed in the ecosystem in early 2017. In addition, this site is applying for the ICOS network labelling as an associated site, and follows the ICOS recommendations. Our main concern is that La Guette peatland is submitted to a strong domination by a herbaceous plant, Molinia caerulea, and a ericaceous shrub, Erica tetralix, which are suspected to modify the C dynamic of the ecosystem. From January 2017 to September 2019, CO2 and CH4 fluxes to the atmosphere ranged from to -19.46 to 19.73 µmol m-2 s-1 and from -0.12 to 0.42 µmol m-2 s-1, respectively. Mean CO2 flux for 2017, 2018 and 2019 were respectively 1.13, 1.08 and 0.44 µmol m-2 s-1. Carbon balance of the ecosystem since the beginning of 2017 has been evaluated to 982 gC m-², suggesting that the peatland acted as a source of C over these three last years. In a larger scale, this Eddy covariance station is a part of a French Peatland Observatory Service, and is included in a network of three tower fluxes deployed in three contrasted French peatlands. In the long term, this Eddy-covariance network will provide important data that will help to understand the evolution of the C balance in temperate peatlands with global changes

Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study

Abstract Background Associations between polymorphisms of UDP-glucuronosyltransferases (UGTs) or efflux transporters (e.g., P-glycoprotein and MRP2) and different types of cancer have been described, whereas the role of influx transporters (e.g. OATP1B1 and OATP2B1) has been seldom explored. The GenColon study investigated potential associations between variant alleles of UGTs, efflux and influx transporters and CRC. Methods Three hundred CRC cases were matched with 300 controls for age, sex and enrolment site. Fifteen SNPs in UGT1A6–9, UGT2B7, ABCB1, ABCC2, SLCO1B1 and SLCO2B1 genes were characterized using Taqman® PCR. Using multivariate conditional logistic regression, we investigated the relationships between CRC and “environmental” risk factors (physical activity, housing and working areas, consumption of red meat, tobacco, alcohol); genetic polymorphisms, in the study population and in the subgroups with “environmental” risk factors. Results No significant association was observed for the analyzed SNPs (or haplotypes). However, an increased CRC risk was found in carriers of the UGT1A8 rs1042597-G variant allele (additive risk OR = 3.39[1.29–8.89], p = 0.02951) in the subgroup of meat-consumers (n = 84), and in carriers of the ABCB1 rs1045642-T (exon26) variant allele (additive risk; OR = 1.89[1.10–3.39], p = 0.0257) in the “never alcohol consumption subgroup” (n = 125). In addition, as previously reported, the following CRC risk factors were identified: absence of physical activity (OR = 6.35[3.70–10.9], p 30 years (3.37[1.63–6.96], p = 0.0010). Conclusions Variant genotypes of influx transporters (OATP1B1 and 2B1) were not associated with CRC. This study confirmed the influence of lifestyle factors, but not the previously reported detrimental effect of SNPs in intestinal UGTs or efflux transporters, except for a UGT1A8 variant in subjects consuming meat and the exon 26 SNP of ABCB1 in the never alcohol consumption subgroup. Trial registration Registered in Direction Générale de la Santé the 1st July 2008 under the number DGS2008–0144

State-of-the-art methods for exposure-health studies: results from the exposome data challenge event

The exposome recognizes that individuals are exposed simultaneously to a multitude of different environmental factors and takes a holistic approach to the discovery of etiological factors for disease. However, challenges arise when trying to quantify the health effects of complex exposure mixtures. Analytical challenges include dealing with high dimensionality, studying the combined effects of these exposures and their interactions, integrating causal pathways, and integrating high-throughput omics layers. To tackle these challenges, the Barcelona Institute for Global Health (ISGlobal) held a data challenge event open to researchers from all over the world and from all expertises. Analysts had a chance to compete and apply state-of-the-art methods on a common partially simulated exposome dataset (based on real case data from the HELIX project) with multiple correlated exposure variables (P>100 exposure variables) arising from general and personal environments at different time points, biological molecular data (multi-omics: DNA methylation, gene expression, proteins, metabolomics) and multiple clinical phenotypes in 1301 mother-child pairs. Most of the methods presented included feature selection or feature reduction to deal with the high dimensionality of the exposome dataset. Several approaches explicitly searched for combined effects of exposures and/or their interactions using linear index models or response surface methods, including Bayesian methods. Other methods dealt with the multi-omics dataset in mediation analyses using multiple-step approaches. Here we discuss features of the statistical models used and provide the data and codes used, so that analysts have examples of implementation and can learn how to use these methods. Overall, the exposome data challenge presented a unique opportunity for researchers from different disciplines to create and share state-of-the-art analytical methods, setting a new standard for open science in the exposome and environmental health field

State-of-the-art methods for exposure-health studies: Results from the exposome data challenge event

International audienceThe exposome recognizes that individuals are exposed simultaneously to a multitude of different environmental factors and takes a holistic approach to the discovery of etiological factors for disease. However, challenges arise when trying to quantify the health effects of complex exposure mixtures. Analytical challenges include dealing with high dimensionality, studying the combined effects of these exposures and their interactions, integrating causal pathways, and integrating high-throughput omics layers. To tackle these challenges, the Barcelona Institute for Global Health (ISGlobal) held a data challenge event open to researchers from all over the world and from all expertises. Analysts had a chance to compete and apply state-of-the-art methods on a common partially simulated exposome dataset (based on real case data from the HELIX project) with multiple correlated exposure variables (P > 100 exposure variables) arising from general and personal environments at different time points, biological molecular data (multi-omics: DNA methylation, gene expression, proteins, metabolomics) and multiple clinical phenotypes in 1301 mother-child pairs. Most of the methods presented included feature selection or feature reduction to deal with the high dimensionality of the exposome dataset. Several approaches explicitly searched for combined effects of exposures and/or their interactions using linear index models or response surface methods, including Bayesian methods. Other methods dealt with the multi-omics dataset in mediation analyses using multiple-step approaches. Here we discuss features of the statistical models used and provide the data and codes used, so that analysts have examples of implementation and can learn how to use these methods. Overall, the exposome data challenge presented a unique opportunity for researchers from different disciplines to create and share state-of-the-art analytical methods, setting a new standard for open science in the exposome and environmental health field

BRAF V600E-Mutant Colorectal Cancers with Liver-Only Metastases: A Retrospective Study.

International audienceAbstract BACKGROUND BRAF V600E-mutant colorectal cancers (CRCs) are associated with shorter survival than BRAF wild-type tumors. Therapeutic decision-making for colorectal liver metastases (CRLM) harboring this mutation remains difficult due to the scarce literature. Our aim was to study a large cohort of BRAF V600E-mutant CRLM patients in order to identify prognostic factors associated with overall survival. METHODS We retrospectively identified BRAF V600E-mutant CRCs diagnosed with liver-only metastases, resected or not, between April 2008 and December 2017, in 25 French centers. Clinical, molecular, pathological characteristics and treatment features were collected. Overall survival (OS) was defined as the time from CRLM diagnosis to death from any cause. Cox proportional hazard models were used for statistical analysis. RESULTSAmong the 105 patients included, 79 (75%) received chemotherapy, 18 (17%) underwent upfront CRLM surgery, and 8 (8%) received exclusive best supportive care. CRLM surgery was performed in 49 (46.7%) patients. CRLM were mainly synchronous (90%) with bilobar presentation (61%). The median OS was 34 months (range, 28.9–67.3 months) for resected patients and 10.6 (6.7–12.5) months for unresected patients ( P < 0.0001). Most patients received doublet chemotherapy (72%), and 34% received a combination with bevacizumab as a first-line treatment. In multivariate analysis, primary tumor surgery (hazard ratio (HR) = 0.349; 95% confidence interval (CI) 0.164–0.744, P = 0.0064) and CRLM resection (HR = 0.169; 95% CI 0.082–0.348, P < 0.0001) were associated with significantly better OS. CONCLUSIONSIn the era of systemic cytotoxic chemotherapies, liver surgery seems to extend OS. Therefore, CRLM resectability should be assessed, regardless of mutational status

Prognostic factors of BRAF V600E colorectal cancer with liver metastases: a retrospective multicentric study

International audienceBACKGROUND: BRAF V600E-mutant colorectal cancers (CRCs) are associated with shorter survival than BRAF wild-type tumors. Therapeutic decision-making for colorectal liver metastases (CRLM) harboring this mutation remains difficult due to the scarce literature. The aim was to study a large cohort of BRAF V600E-mutant CRLM patients in order to see if surgery extend overall survival among others prognostic factors. METHODS: BRAF V600E-mutant CRCs diagnosed with liver-only metastases, resected or not, were retrospectively identified between April 2008 and December 2017, in 25 French centers. Clinical, molecular, pathological characteristics and treatment features were collected. Overall survival (OS) was defined as the time from CRLM diagnosis to death from any cause. Cox proportional hazard models were used for statistical analysis. RESULTS: Among the 105 patients included, 79 (75%) received chemotherapy, 18 (17%) underwent upfront CRLM surgery, and 8 (8%) received exclusive best supportive care. CRLM surgery was performed in 49 (46.7%) patients. CRLM were mainly synchronous (90%) with bilobar presentation (61%). The median OS was 34 months (range, 28.9-67.3 months) for resected patients and 10.6 (6.7-12.5) months for unresected patients (P &lt; 0.0001). In multivariate analysis, primary tumor surgery (hazard ratio (HR) = 0.349; 95% confidence interval (CI) 0.164-0.744, P = 0.0064) and CRLM resection (HR = 0.169; 95% CI 0.082-0.348, P &lt; 0.0001) were associated with significantly better OS. CONCLUSIONS: In the era of systemic cytotoxic chemotherapies, liver surgery seems to extend OS in BRAF V600E-mutant CRCs with liver only metastases historical cohort

Aspirin versus placebo in stage III or high-risk stage II colon cancer with PIK3CA mutation: a French randomised double-blind phase III trial (PRODIGE 50-ASPIK)

IF 3.061International audienceOxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. Two recent retrospective studies strongly suggested that low-dose aspirin used (100 mg/d) after surgical resection of colorectal cancer with a PIK3CA mutation could act as a targeted therapy with a major protective effect on the risk of recurrence. We propose a double-blind randomized phase III study to evaluate aspirin (100 mg/d during 3 years or until recurrence) versus placebo. Main inclusion criteria are patients aged 18 or 20, stage III or high risk stage II. The primary endpoint of the study is 3-year disease-free survival (DFS). Hypotheses are to improve 3-years DFS from placebo: 72% to aspirin: 83% (HR = 0.56). 94 events and 264 patients with PIK3CA mutation are required. The secondary endpoints are DFS at 5 years, the overall survival rate at 5 years, grade 3-4 severe bleeding

Additional file 1: Table S1. of Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study

SNPs studied and their frequencies in our population. This table contains the description and frequencies of the SNP investigated in the study for ABCB1, UGT, MRP2, SLCO1B1 and SLCO1B2 genes. (DOCX 22 kb